A breakdown in the immunotolerogenic function of the placenta may result in a failure of the placenta to adequately protect the fetus against possible harmful effects of the maternal immune system. This could in turn contribute to certain pathologies of the placenta such as intrauterine growth retardation and preeclampsia, complications that not only put the mother' s health at risk, but also may have long-term effects on the health of the child. Recent studies have unveiled the existence of multiple cell surface-associated proteins belonging to the B7 and CD28 families that are of fundamental importance in immunological tolerance. Our preliminary studies have shown that these molecules are strong candidates for modulation of the maternal immune system by fetal trophoblast cells. In AIM 1 of this proposal, we will map the cellular sources of (a) the B7 family ligands, B7-DC and B7-H2, and (b) their CD28 receptors, PD-1 and ICOS, at the human maternal-fetal interface. Placental tissues and subpopulations of cells of the maternal-fetal interface will be examined for B7 and CD28 family member expression using molecular and histological techniques. In AIM 2, we will elucidate the mechanisms of regulation of BT-H1 and BT-H2 in trophoblast cells. This aim will determine the molecular and cellular mechanisms by which these molecules are regulated. AIM 3 will be to determine the functional effects of B7-H1 and B7-H2 on lymphocyte death, proliferation, and cytokine production. In these studies, human trophoblast cell culture models will be used to dissect the molecular and cellular consequences of signaling from trophoblast B7-H1 and B7-H2 to lymphocytes. Lastly, AIM 4 will evaluate the consequences of disruption of B7-H1 and B7-H2 signaling on cytokine production, leukocyte infiltration, and fetal viability in pregnant mice. In this aim, post-implantation pregnant mice will be treated with neutralizing antibodies and will be evaluated for these reproductive parameters. These studies are expected to yield a wealth of insight on the mechanisms by which successful pregnancy is permitted despite the allogeneic incompatibility between mother and fetus. Further, these studies will advance our knowledge in developing therapies for infertility and a wide range of other ailments such as cancer and autoimmune disease. [unreadable] [unreadable]